BCMA target is strong, who can be proud of the arena?

Recently, news of BCMA targets has continued
.

On June 1, the US FDA granted Janssen a breakthrough therapy designation (BTD) for Teclistamab (JNJ-64007957).

As a key diagnostic marker and treatment target for multiple myeloma (MM), BCMA has been deployed by many companies one after another
.

At present, CAR-T cell therapy and ADC drugs targeting BCMA have been approved for marketing, and dual-antibody drugs are gaining momentum

01 BCMA

The full name of BCMA is B cell maturation antigen, which is a member of the tumor necrosis factor receptor family
.

BCMA is mainly expressed on the surface of late-stage B cells, short-lived proliferating plasmablasts and long-lived plasma cells, but not on naive B cells, CD34-positive hematopoietic stem cells and other normal tissue cells

The main ligands of BCMA are BAFF and APRIL
.

When BCMA is combined with BAFF, it can activate the classical and non-canonical NF-κB pathway and JNK signaling pathway, up-regulate the expression of anti-apoptotic proteins, and down-regulate the expression of pro-apoptotic proteins; when BCMA is combined with APRIL, the expression level of immune checkpoints will be up-regulated , To create an immunosuppressed bone marrow microenvironment

02 BCMA ADC

Blenrep (Belantamab mafodotin, GSK2857916) is a BCMA ADC drug developed by GSK, and it is also the world's first BCMA ADC drug
.

In August 2020, Blenrep was approved for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who had previously received at least four therapies

Blenrep structure:

(1) Antibody: J6M0 is a fully humanized anti-BCMA monoclonal antibody, which enhances the binding ability of monoclonal antibody FcR through desalination and alcosylation in the Fc region, and can more effectively block the binding of BCMA to BAFF/APRIL The downstream pathway of activated NF-kB down-regulates the expression of anti-apoptotic proteins and up-regulates the expression of pro-apoptotic proteins
.

       (2) Linker: Linker cannot be split and has no bystander effect
.

       (3) Payload: Blenrep uses MMAF as its payload.
MMAF is a tubulin inhibitor that can inhibit cell division by blocking microtubule polymerization, stop tumor cells in G/M phase and induce apoptosis, DAR=4
.

       Blenrep's approval for marketing is based on the pivotal DREAMM-2 study.
A total of 196 patients with R/R MM who have been over-treated in the past were enrolled in the trial, and they had received 7 median treatment options in the past
.

The test results showed that the overall remission rate of Blenrep 2.

       In terms of adverse events, Blenrep grade 3 or above adverse events include corneal lesions/microcystic epithelial changes (MEC; 46%), thrombocytopenia (22%), anemia (21%), decreased lymphocyte count (13%), and Decreased neutrophils (11%)
.

Nearly half of the subjects had to endure the ocular toxicity of corneal lesions, and the safety of Blenrep was unbelievable

       In 2020, ASCO also announced the data of Blenrep combined with bortezomib/dexamethasone in the treatment of MM.
The overall ORR of the combined program reached 78% and the VGPR reached 50%
.

The overall efficacy data is very eye-catching, but the incidence of adverse events has increased accordingly.

       03 BCMA double antibody

       The BCMA double antibody can simultaneously target BCMA on myeloma cells and CD3 on T cells, and kill myeloma cells with high BCMA expression by recruiting T cells.
Currently, no CD3×BCMA double antibody product has been approved for marketing
.
A number of multinational giants have deployed BCMA dual antibodies, including Regeneron, AbbVie, Janssen, Pfizer, and Amgen
.
Domestic BeiGene (AMG701 introduced by Amgen) and Anmin Biotech (EMB-06) have also deployed this dual-antibody target combination
.

       From the design point of view, most of the double-antibody products are administered intravenously, while the double-antibody products of Janssen and Pfizer are administered subcutaneously.
Subcutaneous administration is expected to reduce the high toxic and side effects of intravenous administration and improve drug safety
.

       From the analysis of effectiveness data, Janssen’s Telistamab has an overall ORR of 65%, followed by Abbvie’s TNB-383B, which has an ORR of 52%.
From a safety point of view, the double antibody products of Janssen, AbbVie, and Regeneron, despite their blood toxicity High, but CRS and NT of grade 3 or above have not been observed so far, and the safety is relatively high
.
Pfizer’s PF-06863135 was suspended due to the discovery of 3 cases of weekly neuralgia adverse reactions in the phase II clinical trial.
Amgen’s AMG701 suspended the enrollment of patients due to the risk of CRS, and AMG420 was suspended due to the short half-life of the BiTE platform
.

       For double antibody products, the speed of research and development is the first element
.
At present, CD3×BCMA's dual-antibody layout has been slightly crowded.
For the competition between the dual-antibody, perhaps the best strategy is to take the lead in listing with good Phase II data, and the key to taking advantage of the first-mover advantage to seize the market
.
The superiority is similar to the mechanism of action, and the clinical efficacy of dual antibodies is not as good as CAR-T therapy.
It is expected that it will be difficult to match CAR-T therapy in the future
.
In the face of CAR-T competition, dual antibodies may be matched by a low-price strategy.
After all, the current autologous CAR-T is too expensive and has low universality
.

       04 BCMA CAR-T

       Abecma is the first CAR-T therapy targeting B cell maturation antigen (BCMA), which is jointly developed by BMS and Bluebird and is approved for marketing.
The indication is MM
.
The approval of Abecma is based on KarMMa's pivotal Phase II clinical trial, with an overall ORR of 72% and a CR of 28%, and the efficacy data is very eye-catching
.
In terms of safety, the incidence of Grade ≥3 CRS was 9%, one of the patients had Grade 5 CRS, and the incidence of Grade ≥3 NT was 4%
.
The core reason why CAR-T therapy is significantly better than dual antibodies and ADC drugs is that CAR-T can recognize and kill tumor cells in a non-MHC restricted manner, and it also has the ability to recognize and kill tumor cells with low expression of target antigen
.

       However, Abecma’s pricing is too high, with a total price of US$419,500, which may be twice the price of bi-antibody therapy
.
Johnson & Johnson/Legendary Bio's BCMA CAR-T is also in hot pursuit.
It has submitted a BLA application to the FDA in December 2020.
According to the latest data disclosed by 2021ASCO, the ORR is 95%, the CR is 75%, and the CRS is level 3 or above.
The incidence rate is 10%, and there is no neurotoxicity (NT) above grade 3.
The data has obvious advantages over Abecma
.
In addition, the drug is exploring the adaptability of outpatient medication, and it is expected to reduce the overall cost of CAR-T drugs in the future
.

       05 Summary

       The treatment method targeting BCMA is showing a flourishing prosperity.
A new generation of therapies such as double antibodies, ADC and CAR-T are all on the battlefield.
From the perspective of curative effect, CAR-T therapy is distinguishing itself by virtue of its higher ORR and CR.
Security risks, including CRS and NT risks, should not be underestimated
.
The double antibody and ADC drugs are not to be outdone, and the combination plan is expected to further improve the efficacy, but the increased safety risk is also worth considering
.
However, the exact geometry of the BCMA track is still worthy of in-depth discussion.
After all, whether it is CAR-T therapy, or double antibodies and ADC, all have been approved for MM indications that have received four or more therapies in the past.
Limited
.
Perhaps, who can be the first to be approved for front-line indications and be the first to shake the position of lenalidomide, bortezomib, daretuzumab and other drugs, who can truly be proud of the world
.